(S)-Phenylacetylcarbinol is a valuable chiral building block in organic syntheses and can be used for synthesis of fine chemicals and pharmaceuticals. According to the prior art to date, no methods are known in which (S)-phenylacetylcarbinol (S)-PAC can be generated in optical purities of >89% ee by asymmetric synthesis from non-chiral, inexpensive compounds. However, high optical purities are of decisive importance in the production of fine chemicals or pharmaceuticals.
According to the prior art, various methods are known for producing (S)-phenylacetylcarbinol.
On the one hand chemical syntheses are known.
The methods for producing (S)-PAC based on chemical asymmetric synthesis generate an ee of 68% or 86%. The methods are described in the publications of Davis, Franklin A.; Sheppard, Aurelia C; Lal, G. Sankar Tetrahedron Letters, 1989, vol. 30, 7 p. 779-782 and Adam, Waldemar; Fell, Rainer T.; Stegmann, Veit R.; Saha-Moeller, Chantu R. Journal of the American Chemical Society, 1998, vol. 120, 4 p. 708-714. There are furthermore methods in which (S)-PAC is formed only as a by-product and (R)-PAC is present in an enantiomeric excess, such as for example in the following reactions, such as the reduction of 1-phenylpropane-1,2-dione, which is described in the publications of Toukoniitty, Esa; Maeki-Arvela, Paeivi; Kuzma, Marek; Villela, Alexandre; Kalantar Neyestanaki, Ahmad; Salmi, Tapio; Sjoeholm, Rainer; Leino, Reko; Laine, Ensio; Murzin, Dmitry Yu, Journal of Catalysis, 2001, vol. 204, 2 p. 281-291, and the synthesis starting from benzaldehyde, which is described by Fleming, Steven A.; Carroll, Sean M.; Hirschi, Jennifer; Liu, Renmao; Pace, J. Lee; Redd, J. Ty Tetrahedron Letters, 2004, vol. 45, 17 p. 3341-3343, and the reaction of 2-hydroxy-2-phenylacetonitrile of Brussee, J.; Roos, E. C; Gen, A. Van Der Tetrahedron Letters, 1988, vol. 29, 35 p. 4485-4488.
A synthesis is moreover described in which the chiral building block 1-phenylpropane-1,2-diol can be oxidized to (S)-PAC. (S)-PAC is formed with an enantiomeric excess (ee) of 91%, as described by Zi-Qiang Rong, Hui-Jie Pan, Hai-Long Yan, and Yu Zhao Organic Letters, 2014, 16 (1), pp 208-211, or 69%, as has been described by Waldemar Adam, Chantu R. Saha-Möller, and Cong-Gui Zhao Journal of Organic Chemistry, 64 (20), 7492-7497; 1999, but in addition is contaminated with a regioisomer which must be separated off in a cumbersome manner.
An enzymatic asymmetric synthesis is furthermore known, which is described in the 2013 dissertation of Álvaro Gómez Baraibar entitled “Development of a biocatalytic production process for (S)-alpha-hydroxy ketones”. If this enzyme expressed according to this dissertation heterologously in Escherichia coli is used for the synthesis in whole cells, the optical purity of (S)-PAC is ˜43% ee.
This sole enzymatic asymmetric synthesis of (S)-PAC was described in a carboligation reaction starting from benzaldehyde and acetaldehyde, or benzaldehyde and pyruvate. The reaction is catalyzed by a variant of the enzyme pyruvate decarboxylase from Acetobacter pasteurianus, ApPDC-E469G, in which glutamate is replaced by glycine in position 469. The highest enantiomeric excess which has been achieved with the isolated enzyme in this context is 89%, as described by Rother Nee Gocke, Doerte; Kolter, Geraldine; Gerhards, Tina; Berthold, Catrine L.; Gauchenova, Ekaterina; Knoll, Michael; Pleiss, Juergen; Mueller, Michael; Schneider, Gunter; Pohl, Martina in the publication in ChemCatChem, 2011, vol. 3, 10 p. 1587-1596.